JP2021004237A - Topical compositions containing n-acyl dipeptide derivatives and glycolic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition for topical use. The present invention provides a topical composition comprising a combination of an N-acyldipeptide derivative and glycolic acid. The composition enhances the penetration of N-acyldipeptide derivatives into the skin. [Selection diagram] None

Description

The present invention provides a topical composition comprising a combination of an N-acyldipeptide derivative and glycolic acid. The composition enhances the penetration of the dipeptide derivative into the skin.

U.S. Pat. No. 9,067,969 discloses a variety of N-acyldipeptide derivatives for treating diseases and diseases ranging from cancer and immune diseases to skin system conditions and diseases. Patent '969 specifically discloses a subset of N-acyldipeptide derivatives containing valine (Val) and alanine (Ala) as preferred compounds for treating aging-related skin changes. The '969 patent discloses various routes of administration for this purpose, including those for topical use. Topical compositions such as solutions, gels, lotions, creams, emulsions, etc. have been disclosed, and the amount of N-acyldipeptide derivative in such compositions is 0.001% by volume or% by volume to 99% by volume of the total composition. It can be in the range of 9.9 weights or percent by volume. The patentee also discloses that these compositions may contain other cosmetics or agents containing hydroxy acids such as glycolic acid, among hundreds of other agents.

The '969 patented dipeptide derivative contains alkaline radicals such as amino groups modified by acylation, and as a result, it is no longer amphoteric in nature and therefore more easily penetrates the skin, but with improved skin penetration properties. Still desired.

Applicants have now found improved compositions and methods for increasing skin penetration of Val and Ala-containing N-acyldipeptide derivatives. Specifically, Applicants have found that when combined with a particular amount of glycolic acid, the penetration of these compounds is surprisingly increased. Accordingly, novel compositions and methods utilizing a combination of N- acyl dipeptide derivatives and glycolic acid of the formula _R 1 _{-Val-Ala-R 2} is provided.

The present invention is a topical composition, the formula:
R _1- Val-Ala-R ₂
In the formula, Val is valine, Ala is alanine, and R ₁ is an acyl radical having a maximum of 19 carbon atoms. , R ₂ is OR ₃ , NHR ₄ , or NNHHR ₅ , R ₃ is H, an alkyl, aralkyl, or aryl radical with up to 19 carbon atoms, and R ₄ and R ₅ are independent, respectively. The composition comprises H, OH, an alkyl, aralkyl, aryl, or acyl radical having a maximum of 19 carbon atoms, an N-acyldipeptide derivative or an isomer or salt thereof, and a glycolic acid. However, topical compositions comprising up to about 10 weight percent glycolic acid are provided.

The present invention is also a method of treating signs of skin aging, comprising topically applying a topical composition to the skin in which at least one sign of skin aging needs to be treated. The required composition is:
R _1- Val-Ala-R ₂
A N- acyl dipeptide derivatives or an isomer or salt having the formula, Val is valine, Ala is alanine, R ₁ is an acyl radical having up to 19 carbon atoms , R ₂ is OR ₃ , NHR ₄ , or NNHHR ₅ , R ₃ is H, an alkyl, aralkyl, or aryl radical with up to 19 carbon atoms, and R ₄ and R ₅ are independent, respectively. The composition comprises H, OH, an N-acyldipeptide derivative or an isomer or salt thereof, which is an alkyl, aralkyl, aryl, or acyl radical having a maximum of 19 carbon atoms, and a glycolic acid. However, a method is provided that comprises up to about 10 weight percent glycolic acid.

The present invention further describes the formula:
R _1- Val-Ala-R ₂
A method for increasing the penetration of an N-acyldipeptide derivative or an isomer or salt thereof into the skin, wherein Val is valine, Ala is alanin, and R ₁ is up to 19 in the formula. R ₂ is OR ₃ , NHR ₄ , or NHNHR ₅ , and R ₃ is H, an alkyl, aralkyl, or aryl radical with up to 19 carbon atoms. R ₄ and R ₅ are independently H, OH, alkyl, aralkyl, aryl, or acyl radicals having up to 19 carbon atoms, the method of which is a topical composition comprising glycolic acid. Provided is a method comprising topically administering an N-acyldipeptide derivative to the skin, wherein the amount of the glycolic acid is up to about 10% by weight of the composition.

Unless otherwise specified, all technical and scientific terms used herein have the meaning generally understood by those skilled in the art to which the present invention belongs. All publications, patent applications, patents, and other references referred to herein are incorporated herein by reference.

As used herein, "topically applied" means applying or spreading directly to the exodermis, scalp or hair, for example by hand or by using an applicator such as a wipe, roller or spray. Means.

As used herein, "cosmetically acceptable" means that the ingredients described by this term are free of excessive toxicity, incompatibility, instability, irritation, allergic reactions, and tissues (eg, skin or It means that it is suitable for use in contact with hair).

As used in the present invention, a "cosmetically acceptable activator" is a compound (synthetic or natural) having a cosmetic or therapeutic effect on the skin or hair.

The compositions of the present invention are suitable for treating signs of skin aging. As used herein, "signs of skin aging" include the presence of wrinkles, including fine wrinkles and deep wrinkles, loss of elasticity, uneven skin, stains, reduced skin thickness, and collagen, glycosaminoglycans, Includes abnormal synthesis or decreased synthesis of glycoproteins, including proteoglycans, elastin, or fibronectin. In one embodiment, signs of aging are selected from the presence of wrinkles, fine lines, deep wrinkles, loss of elasticity, and abnormal synthesis or decreased synthesis of glycoproteins, including collagen, glycosaminoglycans, proteoglycans, elastin, or fibronectin. Will be done.

As used herein, "treating" or "treating" means ameliorating, preventing, or ameliorating a condition, disease or illness, or at least one of these recognizable symptoms. In one embodiment, "treatment" or "treatment" is at least one measurable condition, disease, or disease associated with the treated condition, disease, or disease that is not necessarily recognizable by or by the subject being treated. Refers to the improvement, prevention, or recovery of various physical parameters. In another embodiment, "treatment" or "treatment" is either physically (eg, stabilizing recognizable symptoms), physiologically (eg, stabilizing physical parameters), or both. Refers to inhibiting or delaying the progression of a condition, disease or disease. In another embodiment, "treating" or "treating" refers to delaying the onset of a condition, disease or disease.

In certain embodiments, the compositions of the invention are administered as a prophylactic measure. As used herein, "preventing" or "preventing" refers to reducing the risk of contracting a given condition, disease, or disease.

In a broader sense, the compositions of the present invention also include skin, nail, and hair-related infections, disordered or disordered skin or mucosal tissues; oral, vaginal, and anal mucosa; interfering with keratinization; inflammation; Cosmetic, dermatological, cosmetic, dermatological, including but not limited to changes associated with intrinsic and extrinsic aging, as well as others that may or may not be associated with the skin system. Or it can be used to treat or prevent other conditions and illnesses. Findings include greasy skin; acne; liquor; senile pigmented spots; stained skin; stains; cellulite; dermatitis; dermatitis; skin, nail, and hair infections; fluff; skin, nails, and hair Dryness or sagging; dryness; inflammation or eczema; elastic fibrosis; herpes; hyperlipidemia; excessively pigmented skin; fish scales; keratosis; kuroko; melanosis; patchy skin; Photoaging and photodamage; pruritus; psoriasis; skin wrinkles; stretch marks; skin, nail plate, and hair thinning; irritation; deep wrinkles; oral or gingival disorders; irritated, inflamed Red, unhealthy, damaged or abnormal mucous membrane, skin, hair, nails, nasal passages, external auditory canal, anus, or vaginal condition; destruction of skin components, synthetic deficiency, or repair; collagen, glycosaminoglycan, proteoglycan , And abnormal synthesis or reduction of synthesis of elastin, and reduced levels of such components in the dermatitis; uneven skin tone; uneven and rough surface of skin, nails, and hair; skin, nails, and Loss or reduction of elasticity, elasticity, and resilience of hair; looseness; lack of lubricity and luster of skin, nails, and hair; brittle, fragile nails and hair; yellowing skin; reactive, irritating, or Capillary dilated skin; and includes, but is not limited to, dull, older-looking skin, nails, and hair. In addition, the compositions of the present invention are for general care of the skin, nails, and hair; to improve the texture and pores of the skin, the ease of peeling and redness; the skin is soft, smooth and fresh. To make the skin balanced, visually transparent, uniform in color, and brighter; to increase the plumpness and plumpness of the skin; and to whiten and color the skin. For thinning and wound healing; can be used to reduce or prevent sweating or evaporation of the armpits, crotch, palms, or other parts of the body.

As used herein, the term "subject" means any animal, preferably a mammal, most preferably a human, to which the composition of the invention has been administered or administered. As used herein, the term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans. In a preferred embodiment, the subject is a human.

As used in the present invention, "wrinkles" include fine wrinkles, fine wrinkles, or coarse wrinkles. Examples of wrinkles include, but are not limited to, fine wrinkles around the eyes (eg, "crow's footprints"), wrinkles on the forehead and cheeks, wrinkles between the eyebrows, and age lines around the mouth.

As used in the present invention, "loss of elasticity" includes, but is not limited to, loss of elasticity or structural integrity of skin or tissue, including, but not limited to, sagging, relaxation, and loose tissue. Loss of elasticity or structural integrity of tissue includes, but is not limited to, the consequences of disease, aging, hormonal changes, mechanical trauma, environmental damage, or application of products such as cosmetics or pharmaceuticals to tissue. , Can be the result of a number of factors.

As used in the present invention, "heterogeneous skin" means a skin condition associated with diffuse or speckled pigmentation that can be classified as hyperpigmented, such as post-inflammatory hyperpigmentation.

As used in the present invention, "blemishes" means skin conditions associated with redness or erythema.

As used in the present invention, "cosmetic", specifically when it comes to the appearance of tissues or skin, maintains, restores, gives, dresses or enhances, or is beautiful or youthful. Refers to a beautifying substance or formulation that appears to increase in taste.

When used in the present invention, a "cosmetically effective amount" is an amount sufficient to treat or prevent one or more signs of skin aging, but low enough to avoid severe side effects. Means. The cosmetically effective amount of the compound or composition is the specific condition to be treated, the age and health of the end user, the severity of the condition to be treated / prevented, the duration of treatment, the nature of other treatments, the specifics to be used. It depends on the compound or product / composition of the product, the specific cosmetic carrier used, and similar factors.

Unless otherwise indicated, percentage or concentration refers to weight percentage or weight concentration (ie,% (W / W)). Unless otherwise specified, the entire range includes endpoints, eg, "4-9" includes endpoints 4 and 9.

The N-acyldipeptide derivative composition has the formula:
R _1- Val-Ala-R ₂
One or more N-acyldipeptide derivatives or isomers or salts thereof having, in the formula, Val is valine, Ala is alanine, and R ₁ has a maximum of 19 carbon atoms. It is an acyl radical, R ₂ is OR ₃ , NHR ₄ , or NHNHR ₅ , and R ₃ is H, an alkyl, aralkyl, or aryl radical with up to 19 carbon atoms, R ₄ and R ₅ Each independently comprises one or more N-acyldipeptide derivatives or isomers or salts thereof, which are H, OH, alkyl, aralkyl, aryl, or acyl radicals having up to 19 carbon atoms. The above-mentioned mixture may be used.

In one embodiment, the dipeptide derivative is N-Ac-Val-Ala-NH ₂ , N-Ac-Val-Ala-OH, N-Ac-Val-Ala-NHOH, N-Pr-Val-Ala-NH ₂ , And N-Pr-Val-Ala-OH, in which Ac is acetyl and Pr is propanoyl.

In another embodiment, the dipeptide derivative is N-Ac-Val-Ala-NH ₂ , where in the formula Ac is acetyl (N-acyl-L-valine-L-alanine amide).

N-acyldipeptide derivatives can be prepared by conventional synthetic methods known in the art.

The amount of N-acyldipeptide derivative in the composition can range, for example, from about 0.001 to about 90 weight percent based on the total weight of the composition. In one embodiment, the amount of N-acyldipeptide derivative in the composition is from about 0.01 to about 2 weight percent based on the total weight in the composition. In a further embodiment, the amount of N-acyldipeptide derivative in the composition is about 0.1 to about 1 weight percent based on the total weight in the composition. In another embodiment, the amount of N-acyldipeptide derivative in the composition is about 0.5 weight percent based on the total weight of the composition.

In one embodiment, the dipeptide derivative is N-Ac-Val-Ala-NH ₂ , and the composition is about 0.1 to about 1, preferably about 0.5 weight percent based on the total weight of the composition. Contains N-Ac-Val-Ala-NH ₂ of.

The glycolic acid composition also contains glycolic acid. The amount of glycolic acid in the composition is about 10 weight percent or less based on the total weight of the composition.

In one embodiment, the composition contains about 1 to about 8 weight percent glycolic acid based on the total weight of the composition.

In another embodiment, the composition contains about 1 to about 4 weight percent glycolic acid based on the total weight of the composition.

Glycolic acid is commercially available from various sources, such as DuPont, as GLYPURE, a 70 weight percent glycolic acid aqueous solution.

Other Cosmeticly Acceptable Activators The composition may contain one or more other cosmetically acceptable activators.

Acceptable cosmetic activators include, for example, anti-acne agents, gloss modifiers, antibacterial agents, anti-inflammatory agents, antifungal agents, antiparasitic agents, topical analgesics, sunscreens, photoprotectants, oxidation. For inhibitors, keratolytics, surfactants, moisturizers, nutrients, vitamins, energy enhancers, antifungals, skin astringents, deodorants, stabilizers, skin hardening inhibitors, and hair and / or skin conditioning Agents can be mentioned.

The amount of other cosmetic activator in the composition is from about 0.001% to about 20% by weight of the composition, for example from about 0.005% by weight of the composition, based on the total weight of the composition. It can range from about 10% by weight, for example from about 0.01% to about 5% by weight of the composition.

Cosmetically acceptable activators include, for example, other alpha hydroxy acids, polyhydroxy acids, other dipeptides, tripeptides, benzoyl peroxides, D-pantenol carotenoids, retinoids such as retinol palmitate and retinyl, ceramides, etc. Polyunsaturated fatty acids, essential fatty acids, enzymes such as lacquer, enzyme inhibitors, minerals, hormones such as estrogen, steroids such as hydrocortisone, 2-dimethylaminoethanol, copper salts such as copper chloride, peptides such as argirelin and syn-ake, Copper-containing substances, amino acids such as coenzyme Q10 and proline, vitamins, lactobionic acid, acetylcoenzyme A, niacin, riboflavin, thiamine, ribose, electron transporters such as NADH and FADH2, aloe vera, nutshirogiku, oatmeal, dill, blackberry , Natural extracts such as those derived from kiri, lemon, aspen, resorcinols such as 4-hexylresorcinol, curcuminoids, sugar amines such as N-acetylglucosamine, and derivatives and mixtures thereof.

Examples of vitamins include vitamin A, B vitamins (eg, vitamin B3, vitamin B5, and vitamin B12), vitamin C, vitamin K, and various forms of vitamin E such as alpha, beta, gamma, or delta tocopherol. , Or mixtures and derivatives thereof, but is not limited thereto.

Examples of other hydroxy acids include, but are not limited to, lactic acid, malic acid, salicylic acid, citric acid and tartaric acid.

Examples of antioxidants are water-soluble antioxidants such as sulfhydryl compounds and their derivatives (eg sodium disulfate and N-acyl-cysteine), lipoic acid and dihydrolipoic acid, resveratrol, lactoferrin, and ascorbic acid. And ascorbic acid derivatives (eg, ascorbyl palmitate and ascorbyl polypeptide), but are not limited thereto. Suitable oil-soluble antioxidants for use in the compositions of the present invention include butylated hydroxytoluene, retinoids (eg, retinol and retinyl palmitate), tocopherols (eg, tocopherol acetate), tocotrienols, and ubiquinone. However, it is not limited to these. Natural extracts containing antioxidants suitable for use in the compositions of the present invention include flavonoids and extracts containing isoflavonoids and derivatives thereof (eg, genistein and daidzein), resveratrol. Examples include, but are not limited to, extracts. Examples of such natural extracts include grape varieties, green tea, pine bark, and propolis.

Topical Compositions The compositions of the present invention are applied topically to the skin or hair. Therefore, the composition may further comprise a cosmetically acceptable topical carrier. The carrier may make up about 25% to about 99.99% by weight of the composition (eg, about 80% to about 99% by weight of the composition). In a preferred embodiment of the invention, cosmetically acceptable topical carriers include water.

In one embodiment, the carrier comprises one or more of glyceryl dilaurate, steareth-10, and glycerin.

Compositions include lotions, creams, gels, sticks, sprays, ointments, cleansing liquid cleaners and solid bars, shampoos and hair conditioners, hair fixers, pastes, foams, powders, mousses, shaving creams, wipes, patches, hydrogels, It may be made into a wide variety of product types including, but not limited to, film forming products, facial and skin masks, films, and make-ups such as foundations and mascaras. Types of these products include, but are not limited to, solutions, suspensions, emulsions such as microemulsions and nanoemulsions, gels, solids, and liposomes, for a variety of cosmetically acceptable topical applications. May contain carriers. The following are non-limiting examples of such carriers. Other carriers can also be blended according to those skilled in the art.

The compositions useful in the present invention can be formulated as a solution. The solution typically comprises an aqueous or organic solvent (eg, about 50% to about 99.99% or about 90% to about 99% cosmetically acceptable aqueous or organic solvent). Examples of suitable organic solvents include propylene glycol, polyethylene glycol, polypropylene glycol, glycerol, 1,2,4-butanetriol, sorbitol ester, 1,2,6-hexanetriol, ethanol, and mixtures thereof. ..

The composition useful for the present invention can be blended as a solution containing a emollient. Such compositions preferably contain from about 2% to about 50% emollient. As used herein, the term "emollient" refers to a material used to prevent or alleviate a dry condition, such as by preventing transdermal water loss from the skin. Examples of emollients include International Cosmetic Ingredient Dictionary and Handbook, Pepe, Wenninger, and McEwen ed., Pp. 2930-36 (The Cosmetic, Toiletry, and France Assist, Washington, DC, 9th Edition, 2002) (hereinafter, "ICI Handbook"), etc., but are limited to this. Not done. Examples of particularly suitable skin softeners include vegetable oils, mineral oils, fatty esters and the like.

Lotions can be made from such solutions. Lotions typically have about 1% to about 20% (eg, about 5% to about 10%) emollients and about 25% to about 90% (eg, about 60% to about 80%). Contains water.

Another type of product that can be formulated from a solution is cream. The cream typically contains about 5% to about 50% (eg, about 10% to about 20%) of emollient and about 25% to about 85% (eg, about 50% to about 75%). Contains water.

The compositions of the present invention may contain water, may otherwise be anhydrous, or do not contain water but contain organic and / or silicone solvents, oils, lipids, and waxes. It may be an ointment. The ointment may contain single base or semi-solid hydrocarbons of animal or vegetable oils. The ointment may contain from about 2% to about 10% emollient and from about 0.1% to about 2% thickener. Examples of thickeners include ICI Handbook's pp. 2979-84, but is not limited to.

The composition may be blended as an emulsion. When the topical carrier is an emulsion, about 1% to about 10% (eg, about 2% to about 5%) of the topical carrier contains an emulsifier. The emulsifier may be nonionic, anionic, or cationic. Examples of emulsifiers include ICI Handbook pp. 2962-71, but is not limited to.

Lotions and creams can be blended as emulsions. Typically, such lotions contain 0.5% to about 5% emulsifier. Such creams typically have about 1% to about 20% (eg, about 5% to about 10%) emollients and about 20% to about 80% (eg, 30% to about 70). %) Water and about 1% to about 10% (eg, about 2% to about 5%) emulsifier.

Oil-in-water and water-in-oil, single-phase emulsion skin care formulations such as lotions and creams are well known in the cosmetics technical field and are useful in the present invention. Polyphasic emulsion compositions such as oil-in-water type or oil-in-oil-in-water type are also useful in the present invention. Generally, such single-phase or polyphase emulsions contain water, emollients, and emulsifiers as essential ingredients.

The compositions of the present invention can also be formulated as gels (eg, aqueous, alcohol, alcohol / water, or oil gels using suitable gelling agents). Suitable gelling agents for aqueous and / or alcoholic gels include, but are limited to, natural rubbers, polymers and copolymers of acrylic acids and acrylates, and cellulose derivatives (eg, hydroxymethyl cellulose and hydroxypropyl cellulose). Not done. Suitable gelling agents for oils (such as mineral oils) include, but are not limited to, hydrogenated butylene / ethylene / styrene copolymers and hydrogenated ethylene / propylene / styrene copolymers. Such gels typically contain from about 0.1% to 5% by weight of such gelling agents.

The composition of the present invention can also be blended into a solid formulation (eg, a wax-based stick, a bar soap composition, a powder, or a wiping product containing the powder).

In addition to the above ingredients, the compositions have established in the art a wide range of additional oil-soluble and / or water-soluble materials conventionally used in compositions for use in skin and hair. It may be contained in a concentration.

Various other materials may also be present in the composition, as is well known in the art. These include moisturizers, pH regulators, chelating agents (eg, EDTA), fragrances, dyes, and preservatives (eg, parabens).

Compositions, formulations and products containing such compositions of the present invention can be prepared using methods well known to those skilled in the art.

In one embodiment, the topical composition comprises an emulsion comprising at least two phases selected from an aqueous phase, an oil phase, and a nonionic lipid phase.

The aqueous phase contains water.

The aqueous phase includes carbomer or other thickeners such as xanthan gum, carrageenan rubber, polyacrylate 13; polyisobutene; polysorbate 20; polyacrylate 13 / polyisobutylene / polysorbate 20 blend, stearalconium hectrite and the like (mixtures thereof). (Including) structural agents may also be contained.

Preferably, the composition comprises a thickener, which is a hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer.

The oil phase contains at least one cosmetically acceptable oil.

As used herein, "oil" means a hydrophobic material that can help balance intermolecular forces in order to form micellar aggregates or limit their size. The oil can also be used as a emollient ingredient to provide product applicability, haptic feel, and delivery of hydrophobic active ingredients such as, but not limited to, vitamins D, E, K, and A, as well as sunscreen filters. Function.

Useful oils in the composition include various hydrocarbon oils ranging from about 20% to 50% based on the total weight of the composition, silicones, fatty acid derivatives, glycerides, vegetable oils, vegetable oil derivatives, alkyl esters, wax esters. , Beeswax derivatives, esters, and phospholipids, and combinations thereof.

Suitable hydrocarbon oils include petrolatum, mineral oils, microcrystalline waxes, squalene, and combinations thereof.

Silicone oils include dimethicone, dimethiconol, phenyldimethicone, and cyclic polysiloxanes, and combinations thereof. Silicone oils with viscosities of about 0.5 to about 100,000 centi-Stokes at 25 ° C. may also be useful in the composition.

Glycerides include castor oil, sunflower seed oil, coconut oil and derivatives, vegetable oils and derivatives, palm oil, jojoba oil, shea butter, lanolin, and combinations thereof.

Alkyl ester oils include, but are not limited to, isopropyl esters of fatty acids and esters of long chain fatty acids. More preferably, the following alkyl esters are useful: isopropyl palmitate, isopropyl myristate, myristyl myristate, isohexyl palmitate, decyl oleate, isononyl isononanoate, and combinations thereof.

The nonionic lipid phase is a glyceryl monoester having a fatty acid chain containing about 3 to about 50 carbon atoms, preferably about 10 to about 18 carbon atoms; about 5 carbon atoms to about 25 carbon atoms. Glyceryl diester having a carbon atom, preferably a fatty acid chain containing about 10 carbon atoms to about 18 carbon atoms; alkoxylated alcohol; alkoxylated alkylphenol; alkoxylated acid; alkoxylated amide; alkoxylated sugar derivative; natural An alkoxylated derivative of oil or wax; polyoxyethylene polyoxypropylene block copolymer; polyoxyethylene ether fatty acid having a fatty acid chain containing about 10 carbon atoms to about 18 carbon atoms; steroid; about 10 fatty acids A fatty acid ester of alcohol; and a combination thereof, which is a linear or branched chain having about 20 carbon atoms and the alcohol is a linear or branched chain having 1 to 10 carbon atoms. It contains one or more nonionic lipids such as, where the alkoxylated lipid is alkoxylated with ethylene oxide or propylene oxide, preferably alkoxylated with ethylene oxide.

Examples of suitable glyceryl monoesters are glyceryl caprate, glyceryl caprylate, glyceryl cocate, glyceryl erucate, glyceryl hydroxystearate, glyceryl isostearate, glyceryl lanophosphate, glyceryl laurate, glyceryl linoleate, glyceryl myristate. , Glyceryl oleate, glyceryl PABA, glyceryl palmitate, glyceryl ricinolate, glyceryl stearate, glyceryl tiglycolate, and mixtures thereof, but are not limited to glyceryl laurate and glyceryl myristate.

Examples of suitable glyceryl diesters include, but are not limited to, glyceryl dilaurate, glyceryl dioleate, glyceryl dimyristate, glyceryl distearate, glyceryl cesiolate, glyceryl lactate stearate, and mixtures thereof. , Glyceryl dilaurate and glyceryl dimyristinate are preferred.

Examples of suitable polyoxyethylene aliphatic ethers are polyoxyethylene cetyl / stearyl ether, polyoxyethylene cholesterol ether, lauric acid or polyoxyethylene dilaurate, stearic acid or polyoxyethylene distearate, polyoxyethylene lauryl or Stearyl ethers and mixtures thereof include, but are not limited to, polyoxyethylene heads range from about 2 to about 100 groups. Preferred polyoxyethylene aliphatic ethers include polyoxyethylene stearyl ethers having about 3 to about 10 oxyethylene units, polyoxyethylene myristyl ethers, and polyoxyethylene lauryl ethers.

Examples of suitable steroids include, but are not limited to, cholesterol, β-sitosterol, bisabolol, and mixtures thereof.

Examples of suitable fatty acid esters of alcohols include isopropyl myristate, aliphatic isopropyl n-butyrate, isopropyl n-hexanoate, isopropyl n-decanoate, isopropyl palmitate, octyldodecyl myristate.

An exemplary alkoxylated alcohol useful as a nonionic lipid in the compositions of the present invention has the following formula:
R ₅ −− (OCH ₂ CH ₂ ) _y −−OH
Has a structure shown in, wherein, R ₅ is a branched or unbranched alkyl group having from about 6 to about 22 carbon atoms, y is from about 4 to about 100, preferably Is about 10 to about 100. Preferred alkoxylated alcohols are, _{R 5} is a lauryl group, a species which has an average value of y is 23, which is known as Laureth 23, ICI Americas, Inc under the trade designation "BRIJ 35". It is available from (Wilmington, Del).

Another representative alkoxylated alcohol is an ethoxylated derivative of a lanolin alcohol. Lanolin alcohol is a mixture of organic alcohols obtained from the hydrolysis of lanolin. An example of an ethoxylated derivative of lanolin alcohol is lanes 10, which is a polyethylene glycol ether of lanolin alcohol having an average ethoxylated value of 10.

Another exemplary alkoxylated alcohol is polyoxypropylene polyoxyethylene alkyl ether, such as PPG-12-Butes 16. This substance is available under the trade name "UCON Fluid 50-HB-660" from Amerchol Corp. It is available from (Edison, NJ).

Another type of nonionic lipid includes an alkoxylated alkylphenol, such as "nonoxynol 14", which is available from Stepan Company (Northfield, Ill) under the trade name "MAKON 14".

Another type of nonionic lipid is an alkoxylated acid, which is an ester of an acid, mostly a normal fatty acid, polyalkylene glycol, eg, PEG-8 laurate.

Another type of nonionic lipid includes an alkoxylated amide, such as PEG-6 cocoamide.

Another type of nonionic lipid includes an alkoxylated sugar derivative, such as polysorbate 20, which is a lauric acid ester of sorbitol and sorbitol, which mainly consists of a monoester condensed with about 20 mol of ethylene oxide. It is a mixture with an anhydride. This substance is available from ICI Americas (Wilmington, Del) under the trade name "TWEEN20".

Another example of an alkoxylated sugar derivative useful in the compositions of the present invention is PEG-20 methylglucose sesquistearate, which is a polyethylene glycol ether of sesquiesters of methylglucose and stearic acid, averaging 20 It contains a molar amount of ethylene oxide and is traded under the trade name "Glucamate SSE-20" by Alkoxy Corp. It is available from (Edison, NJ).

Other types of nonionic lipids include alkoxylated derivatives of natural oils and waxes. Examples of substances in this category include PEG-40 lanolin, PEG-40 castor oil, and PEG-40 cured castor oil.

Other types of nonionic lipids include polyoxyethylene polyoxypropylene block copolymers, such as poloxamer 101 and poloxamer 182.

Preferred nonionic lipids include polyoxyethylene fatty ethers, glyceryl diesters, and mixtures thereof. More preferred nonionic lipids include polyoxyethylene stearyl ether, polyoxyethylene myristyl ether, and polyoxyethylene lauryl ether, glyceryl dilaurate, glyceryl dimistate, glyceryl distearate, and mixtures thereof. , Each ether has about 5 to about 10 oxyethylene units.

In embodiments where reduction of skin irritation is of concern, nonionic lipids with large amounts of carbon atoms in the hydrophilic head portion or, as an alternative, nonionic lipids with large amounts of carbon atoms in the hydrophobic fatty acid chain portion. It is preferable to use lipids. The former can be achieved, for example, by increasing the amount of carbon atoms in the head of the polyoxyethylene-10-stearyl ether from about 10 carbon atoms to about 15-20 carbon atoms. The latter can be achieved, for example, by increasing the amount of carbon atoms in the tail of the 12-carbon fatty acid of the glyceryl diester from about 14 carbons to about 16 carbons.

The compositions of the present invention contain from about 1 percent to about 10 percent, preferably from about 3 percent to about 7 percent nonionic lipids based on the total weight of the composition.

In a preferred embodiment, the nonionic lipid phase comprises water, dilaurate glyceride, steares 10, and glycerin.

pH
In one embodiment, the topical composition has a low pH. For example, the pH may be less than about 4 or less than about 3.3. However, the composition does not have to have a low pH.

Topical compositions may include buffering agents such as lactic acid, citric acid, malic acid, tartaric acid, gluconic acid, or gluconolactone. Preferably, the buffering agent is lactic acid.

Typically, the composition contains about 3 to about 12, or about 4 to about 8 weight percent buffer.

Skin Treatment Methods According to the present invention, signs of skin aging are such that a topical composition comprising the N-acyldipeptide derivatives described herein and up to about 10 weight percent glycolic acid is used in at least one of the skin aging. It can be treated by topical application to the skin where one symptom needs to be treated.

Also, according to the present invention, penetration of the N-acyldipeptide derivative into the skin can be increased by topical administration of the composition also containing up to about 10 weight percent glycolic acid.

In one embodiment, the compositions according to the invention containing an N-acyldipeptide derivative and a composition according to an amount of up to about 10 weight percent glycolic acid contain no glycolic acid or more than 10 weight percent glycolic acid. It increases the cumulative delivery of N-acyldipeptide derivatives to the skin by at least about 2-fold, preferably about 3-fold, or up to 7-fold, as compared to compositions that are contained but otherwise identical.

The present invention will be further described by the following non-limiting examples. The following skin penetration method and high-performance liquid chromatography-mass spectroscopy (HPLC-MS) method were used.

Skin Penetration Methods In vitro skin permeation experiments were performed under the guidelines outlined by the Organization for Economic Cooperation and Development (OECD).

Delaminated human carcass skin specimens were taken with a dermatome to a nominal thickness of 300 μm and stored at −80 ° C. in a solution of Roswell Park Memorial Institute (RPMI) 1640 stored with sodium oxacillin and gentamicin. The entire package with skin (about 1/4 sq ft) from one donor was used in each skin penetration test to supply about 50-60 skin samples per test. When ready for use, the skin was rapidly thawed, rinsed in deionized water, cut into small pieces of approximately 2.25 cm ² and mounted in a static vertical glass Franz diffusion cell. The non-occluded donor compartment consisted of a low glass cap extending 12 mm above the exposed surface area of 0.79 cm ² . The receptor compartment contains 4.5 mL of dalbecolinic acid buffer (pH 7.4) saline containing 0.02% sodium azide to provide a physiologically compatible fluid that slows the growth of microorganisms. It was. Aluminum slots in Pierce Reaction-Therm ™ Heating and Stilring Models (Rockford, IL) where each Franz diffusion cell was set to human body temperature (37 ° C.) to obtain a skin surface temperature of 32 ° C. comparable to in vivo conditions. Placed inside. To ensure homogeneity of the reservoir contents, the receptor solution was stirred at about 400 rpm using a magnetic stir bar.

To ensure that the barrier function is intact, before the beginning of the skin permeation measurements were using tritiated water (3H 2 _O) screening procedure was carried skin integrity test. Ensure partial stratum corneum to mimic the skin condition in vivo, as opposed to performing skin penetration tests on fully hydrated skin immediately after thawing, which would increase skin permeability. Skin samples were equilibrated in Franz diffusion cells for 2 hours to hydrate. An application amount of 150 μL of 3H ₂₀ solution (0.4 μCi / mL) was added to each donor compartment and subsequently removed from the skin surface after a contact time of 5 minutes using a cotton swab. The contents of the receptor compartment were recovered 30 minutes after application and immediately refilled with fresh receptor solution maintained at 37 ° C. Receptor samples were mixed with 10 mL of Ultima Gold XR liquid scintillation cocktail and counted for 1 minute on a Beckman LS6500 liquid scintillation counter. Skin samples that had permeated more than 2.0 μL / cm ² of 3H ₂ O after a 30-minute exposure period were considered unsuccessful for use in skin penetration tests and were replaced with a blank matrix for analytical quantification. It was used as an untreated control to provide or to evaluate the extraction efficiency of test dipeptide derivatives from skin samples. Skin samples through the skin integrity test, and ranked according to 3H 2 _O permeability, to allow comparison of robust treatment effect than for the skin penetration of the dipeptide derivatives, the inherent diversity in skin permeability With consideration, each sample was assigned to a treatment group based on a randomized complete plan design. Franz diffusion cells were washed several times to remove residual 3H, equilibrated overnight and rinsed in the morning with a receptor solution containing 0.1% Ores-20, a soluble enhancer to maintain sink conditions. Used for the remaining skin permeability test.

Semi-solid test formulations were vortexed immediately prior to use and, if necessary, throughout the application regimen to allow the contents to mix well. The designated treatment was applied to the skin sample after the skin sample surface was dried prior to application by gently tapping the skin with a cotton swab. A minimum of 4 repeated tests were performed for each treatment. For all test formulations, 5 μL of test formulation was deposited on the skin with a positive displacement pipette. The formulation was spread evenly over the entire surface area of the exposed tissue (0.79 cm ₂ ) using a glass stir bar pre-moistened with the test formulation. Care was taken to ensure that a viscous application remained on the skin surface and did not follow the walls of the donor chamber. The amount of test formulation added / removed during the spreading procedure was clarified by weight measurement. According to the time required to complete sampling of the terminal receptor compartment 48 hours after application, skin cleansing, tape peeling, and epidermal / dermal skin fractionation to ensure uniform recovery time for all samples. , The application interval was set.

The entire contents of the receptor fluid were recovered at 6, 24 and 48 hours after application and the receptor compartment was replenished with fresh receptor solution after 6 and 24 hours of recovery. After a 48 hour exposure period and sampling of the terminal receptor compartments, the unabsorbed formulation was removed by washing with a mild detergent solution consisting of diluent and 5% Oles-20 in DI water. An aliquot of 300 μL of wash solution was applied to the skin surface using a positive displacement pipette and stirred with a glass stir bar for 30 seconds to mimic the in vivo wash procedure, then using a plastic volumetric pipette from the donor compartment 1 .5 Transferred to Eppendorf tube. The skin was then rinsed twice with an aliquot of 500 μL of DI water, which was stirred on the skin surface with a glass stir bar for 30 seconds and collected in the same tube as the detergent wash. The donor chamber was removed and rinsed with 1.5 mL of 2: 1 methanol: water extraction solvent to collect the residual test article concentrate that had not been absorbed after 48 hours and pipette it into a separate 1.5 Eppendorf tube. I moved it with. Air the skin surface for about 30 minutes to remove potentially unabsorbed application amounts that were not properly removed by skin surface cleansing, or to mimic the amount removed in vivo via desquamation after 48 hours. After drying, the upper layer of the stratum corneum was peeled off with tape. To do this, the skin specimen is placed on a glass plate, D100 D Squame tape is placed on the treated surface area of 0.79 cm ² and uniform with a D-Squame disc applicator for 15 seconds according to the manufacturer's instructions. Pressure was applied. The tape was removed with tweezers and placed in an Eppendorf tube containing a donor chamber rinse, with the sticky side facing inward, while the strip of tape was properly and reliably immersed in the extraction solvent. The epidermis was then carefully peeled from the dermis using tweezers and the separated skin samples were placed in separate short 2 mL vials. 2: 1 Methanol: 1.5 mL of water extraction solvent was added to each vial containing epidermal and dermal skin samples. The dipeptide derivative concentrate in the skin surface wash, tape strip, and skin sample was extracted by shaking the sample on an orbital oscillator at 150 rpm for 24 hours at room temperature. The sample was then filtered through a syringe filter containing a 0.45 μm membrane and collected in a 2 mL HPLC vial for analytical quantification.

To calculate the mass balance, the total content of the analyte in each formulation was measured by pipetting an applied amount of 5 μL into a 1-drum shell vial containing 2 mL of extraction solvent (2: 1 methanol: water). (3 repeated tests per formulation). Samples were previously shaken on an orbital shaker at 150 rpm for 48 hours at room temperature, then filtered through a syringe filter containing a 0.45 μm membrane and collected in a 2 mL HPLC vial for analytical quantification.

High Performance Liquid Chromatography Mass Spectrometry (HPLC-MS) Methods Tape strips (T), dermis (E), recovered using a skin penetration test using high performance liquid chromatography mass spectrometry (HPLC-MS), The amount of N-acetyl-L-valine-L-alanine amide in the dermis (D), wash solution (W), and receptor (R) was analyzed.

2-Acetamide-N- (2-amino-2-oxoethyl) -3-methylbutaneamide (Aurora Fine Chemicals LLC, purity> 95%, batch number A06.430.527_4) was used as the internal standard (IS). System ID number: SK_1519 using an Agilent HPLC / MSD system. The mobile phases used were A: 0.1% formic acid (FA) in water (EMD, HPLC grade, lot number: 57256) (Sigma, reagent grade (> 95%), lot number: SHBJ2924), and B: methanol. It was 0.1% FA (Sigma) and 2 mM ammonium formate (Fluora, HPLC grade, lot number: BCBQ4532V) in (EMD, HPLC grade, lot number: 25777). The column was an Agilent Zorbax Eclipse XDB-C18 column (3.5 μm, 150 × 4.6 mm ID, S / N: USWA016962) and was used at 40 ° C. Two-way gradient elution was used, as shown in Table X. The detector was programmed using the parameters outlined in Table Y.

A standard stock solution (1.0 mg / mL) of N-acetyl-L-valine-L-alanine amide was prepared as follows. About 50 g of N-acetyl-L-valine-L-alanine amide reference standard was placed in a 50 mL volumetric flask and 30 mL of MeOH was added. The mixture was sonicated for 2 minutes, diluted with MeOH to mark and mixed well. After this, the standard stock solution is continuously diluted with a diluent (MeOH: water 2: 1, v / v) to have final concentrations of 0.1, 0.2, 0.5, 2.0, and 5.0 μg / mL. Practical standard (W-STD) and practical quality control standard (W-QC) with final concentrations of 0.3, 1.0, and 4.0 μg / mL were prepared. An internal standard stock solution (1.0 mg / mL) was prepared in MeOH and subsequently diluted with a diluent to prepare an internal working solution (W-IS) at a concentration of 100 ng / mL.

The calibration standard was prepared as follows. 180 μL of diluent was added to a 2.0 mL HPLC vial. Next, 20 μL of W-STD solution or diluent (for blanks) was added, then 800 μL of 100 ng / mL internal standard working solution or diluent (for double blanks) was added and vortexed for 1 minute. Quality control (QC) samples were prepared as follows. 180 μL of epidermis or dermis or lavage fluid or receptor blank matrix was added to a 2.0 mL HPLC vial and 20 μL of W-QC solution was added. 800 μL of 100 ng / mL internal standard working solution was added to the HPLC vial and vortexed for 1 minute.

Test samples were prepared as follows. A 200 μL sample was added to a 2.0 mL HPLC vial. 800 μL of 100 ng / mL internal standard working solution was added and vortexed for 1 minute. The resulting solution was diluted with MeOH: H2O (2: 1, v / v) as needed. Calibration standards, QC samples, and test samples were subjected to HPLC-MS analysis using the above conditions.

A series of test compositions containing N-Ac-Val-Ala-NH ₂ were tested for penetration into human skin samples using skin permeation and HPLC-MS methods. The composition contained the components shown in Tables 1, 2 and 3. The amount of ingredients is reported as a weight percent based on the total weight of the composition. The compositions A to G were for comparison. The composition 1 was according to the present invention.

N-Ac-Val-Ala-NH ₂ is described in Nanjing Pharmatechs Co., Ltd. , Ltd. Obtained from. This was a powder.

Glycolic acid was in the form of a 70 weight percent solution in water (commercially available from GLYPURE, DuPont).

The results are shown in Table 4.

The above results show that Composition 1 containing a combination of N-acetylvalylalanylamide and glycolic acid resulted in the greatest skin penetration of all N-acetylvalylalanylamides tested. Show that. A significantly higher (p <0.01) cumulative amount of dipeptide derivative is delivered to the skin by composition 1 compared to all other compositions, and the highest overall biology of all compositions. The bioavailability was significantly (p <0.05) higher compared to all compositions except composition E, which provided the bioavailability. For example, composition 1 had about 7 times the total bioavailability of the dipeptide derivative delivered to the skin as compared to that provided by composition B.

It may be noted that composition E has four times the total bioavailability of the dipeptide derivative delivered to the skin as compared to composition B, which is glyceryl dilaurate in the formulation. The presence of steareth-10, and one or more of glycerin, also suggests increased delivery of the dipeptide derivative to the skin.

In contrast, increasing the application of N-acetylvalerylalanylamide alone did not increase its skin penetration.

A series containing 0.5% by weight N-Ac-Val-Ala-NH ₂ and 0, 1, 4, 8, or 11% by weight glycolic acid using skin penetration and HPLC-MS methods. The test composition was tested for penetration into human skin samples. The composition contained the components shown in Table 5. The amount of ingredients is reported as a weight percent based on the total weight of the composition. The compositions H to L were for comparison. The compositions 2 to 4 were according to the present invention.

N-Ac-Val-Ala-NH ₂ and glycolic acid were obtained as described in Example 1.

The results are shown in Table 6.

These results indicate that the compositions 2, 3, and 4 containing 1%, 4%, and 8% glycolic acid, respectively, delivered most of the dipeptide derivatives to the skin. Each of these compositions has a significantly higher cumulative amount of dipeptide derivative delivered to the skin (p <0.05) than composition H, which is the same basic formulation containing 0% glycolic acid, and is a dipeptide derivative in the skin. The bioavailable concentration of was significantly higher. For example, compositions 2-4 had about three times the total bioavailability of the dipeptide derivative delivered to the skin as compared to that provided by composition H.

Surprisingly, increasing the glycolic acid concentration to 11% by weight (Composition I) reduces the delivery of the dipeptide derivative to the skin compared to the 1%, 4%, and 8% glycolic acid compositions. And, the delivery of the dipeptide derivative to the skin was significantly reduced (p <0.05) as compared to the 1% and 4% glycolic acid compositions. For example, Composition I had about 2-3 times less total bioavailability of the dipeptide derivative delivered to the skin as compared to that provided by Compositions 2-3.

Furthermore, the composition 3 containing 4% by weight glycolic acid is a dipeptide derivative delivered to the skin as compared to Composition K and Composition L, which each contain 4% by weight gluconolactone and mandelic acid. The bioavailable amount was doubled.

Finally, as indicated by the results of composition J, simply adjusting the pH (pH of the glycolic acid containing the composition) in the basic formulation (composition H) to 3.8 will also deliver to the skin. It did not affect the concentration of dipeptide derivatives.

[Implementation]
(1) A composition for topical use, the formula:
R _1- Val-Ala-R ₂
In the formula, Val is valine, Ala is alanine, and R ₁ is an acyl radical having a maximum of 19 carbon atoms. , R ₂ is OR ₃ , NHR ₄ , or NHNHR ₅ , R ₃ is H, an alkyl, aralkyl, or aryl radical with up to 19 carbon atoms, and R ₄ and R ₅ are independent, respectively. The composition comprises H, OH, an N-acyldipeptide derivative or an isomer or salt thereof, which is an alkyl, aralkyl, aryl, or acyl radical having a maximum of 19 carbon atoms, and a glycolic acid. A topical composition comprising up to about 10 weight percent glycolic acid.
(2) The topical composition according to embodiment 1, which comprises about 1 to about 8 weight percent glycolic acid.
(3) The dipeptide derivative is N-Ac-Val-Ala-NH ₂ , N-Ac-Val-Ala-OH, N-Ac-Val-Ala-NHOH, N-Pr-Val-Ala-NH ₂ , The topical composition according to embodiment 1, wherein Ac is acetyl and Pr is propanoyl, selected from the group consisting of N-Pr-Val-Ala-OH.
(4) The topical composition according to Embodiment 1, wherein the N-acyldipeptide derivative is N-Ac-Val-Ala-NH ₂ , and Ac in the formula is acetyl.
(5) The topical composition according to embodiment 1, further comprising a cosmetically acceptable topical carrier.

(6) The topical composition according to embodiment 5, wherein the carrier comprises one or more of glyceryl dilaurate, steareth-10, and glycerin.
(7) A topical composition of about 0.01 to about 2 weight percent N-Ac-Val-Ala-NH ₂ , wherein in the formula, Ac is acetyl, N-Ac-Val. A topical composition comprising −Ala-NH ₂ , about 1 to about 8 weight percent glycolic acid, and a cosmetically acceptable topical carrier.
(8) A composition for local use, the formula:
R _1- Val-Ala-R ₂
A N- acyl dipeptide derivatives or an isomer or salt having the formula, Val is valine, Ala is alanine, R ₁ is an acyl radical having up to 19 carbon atoms , R ₂ is OR ₃ , NHR ₄ , or NHNHR ₅ , R ₃ is H, an alkyl, aralkyl, or aryl radical with up to 19 carbon atoms, and R ₄ and R ₅ are independent, respectively. Then, H, OH, an alkyl, aralkyl, aryl, or acyl radical having a maximum of 19 carbon atoms, an N-acyldipeptide derivative or an isomer or salt thereof, and glyceryl dilaurate, steareth-10, and glycerin. A topical composition comprising a cosmetically acceptable topical carrier, comprising one or more of the above.
(9) A method for treating a sign of skin aging, which comprises locally applying a topical composition to the skin in which at least one sign of skin aging needs to be treated. Is the formula:
R _1- Val-Ala-R ₂
In the formula, Val is valine, Ala is alanine, and R ₁ is an acyl radical having a maximum of 19 carbon atoms. , R ₂ is OR ₃ , NHR ₄ , or NHNHR ₅ , R ₃ is H, an alkyl, aralkyl, or aryl radical with up to 19 carbon atoms, and R ₄ and R ₅ are independent, respectively. The composition comprises H, OH, an N-acyldipeptide derivative or an isomer or salt thereof, which is an alkyl, aralkyl, aryl, or acyl radical having a maximum of 19 carbon atoms, and a glycolic acid. However, a method comprising up to about 10 weight percent glycolic acid.
(10) The signs of skin aging include wrinkles, fine wrinkles, deep wrinkles, loss of elasticity, uneven skin, stains, reduced skin thickness, and abnormalities in collagen, glycosaminoglycans, proteoglycans, or elastin. The method according to embodiment 9, which is selected from the group consisting of synthetic or reduced synthetic.

(11) The method of embodiment 9, wherein the N-acyldipeptide derivative is locally administered to the skin with about 1 to about 8 weight percent glycolic acid.
(12) The dipeptide derivative is N-Ac-Val-Ala-NH ₂ , N-Ac-Val-Ala-OH, N-Ac-Val-Ala-NHOH, N-Pr-Val-Ala-NH ₂ , 9-Pr-Val-Ala-OH, the method of embodiment 9, wherein Ac is acetyl and Pr is propanoyl, selected from the group consisting of N-Pr-Val-Ala-OH.
(13) The method according to embodiment 9, wherein the N-acyldipeptide derivative is N-Ac-Val-Ala-NH ₂ , and Ac is acetyl in the formula.
(14) Equation:
R _1- Val-Ala-R ₂
A method for increasing the penetration of an N-acyldipeptide derivative or an isomer or salt thereof into the skin, wherein Val is valine, Ala is alanin, and R ₁ is up to 19 in the formula. R ₂ is OR ₃ , NHR ₄ , or NHNHR ₅ , and R ₃ is H, an alkyl, aralkyl, or aryl radical with up to 19 carbon atoms. R ₄ and R ₅ are independently H, OH, alkyl, aralkyl, aryl, or acyl radicals having up to 19 carbon atoms, the method being said to be a topical composition comprising glycolic acid. A method comprising topically administering an N-acyldipeptide derivative to the skin, wherein the amount of the glycolic acid is up to about 10% by weight of the composition.
(15) The method of embodiment 14, wherein the N-acyldipeptide derivative is topically administered to the skin with about 1 to about 8 weight percent glycolic acid.

(16) The dipeptide derivative is N-Ac-Val-Ala-NH ₂ , N-Ac-Val-Ala-OH, N-Ac-Val-Ala-NHOH, N-Pr-Val-Ala-NH ₂ , The method of embodiment 14, wherein Ac is acetyl and Pr is propanoyl, selected from the group consisting of N-Pr-Val-Ala-OH.
(17) The method according to embodiment 14, wherein the N-acyldipeptide derivative is N-Ac-Val-Ala-NH ₂ , and in the formula, Ac is acetyl.

Claims (17)

Topical composition, formula:
R _1- Val-Ala-R ₂
In the formula, Val is valine, Ala is alanine, and R ₁ is an acyl radical having a maximum of 19 carbon atoms. , R ₂ is OR ₃ , NHR ₄ , or NHNHR ₅ , R ₃ is H, an alkyl, aralkyl, or aryl radical with up to 19 carbon atoms, and R ₄ and R ₅ are independent, respectively. The composition comprises H, OH, an N-acyldipeptide derivative or an isomer or salt thereof, which is an alkyl, aralkyl, aryl, or acyl radical having a maximum of 19 carbon atoms, and a glycolic acid. A topical composition comprising up to about 10 weight percent glycolic acid. The topical composition of claim 1, comprising about 1 to about 8 weight percent glycolic acid. The dipeptide derivatives are N-Ac-Val-Ala-NH ₂ , N-Ac-Val-Ala-OH, N-Ac-Val-Ala-NHOH, N-Pr-Val-Ala-NH ₂ , and N-. The topical composition according to claim 1, wherein it is selected from the group consisting of Pr-Val-Ala-OH, in which Ac is acetyl and Pr is propanoyl. The topical composition according to claim 1, wherein the N-acyldipeptide derivative is N-Ac-Val-Ala-NH ₂ , and in the formula, Ac is acetyl. The topical composition according to claim 1, further comprising a cosmetically acceptable topical carrier. The topical composition according to claim 5, wherein the carrier comprises one or more of glyceryl dilaurate, steareth-10, and glycerin. A topical composition of about 0.01 to about 2 weight percent N-Ac-Val-Ala-NH ₂ , wherein in the formula, Ac is acetyl, N-Ac-Val-Ala-. A topical composition comprising NH ₂ , about 1 to about 8 weight percent glycolic acid, and a cosmetically acceptable topical carrier. Topical composition, formula:
R _1- Val-Ala-R ₂
A N- acyl dipeptide derivatives or an isomer or salt having the formula, Val is valine, Ala is alanine, R ₁ is an acyl radical having up to 19 carbon atoms , R ₂ is OR ₃ , NHR ₄ , or NHNHR ₅ , R ₃ is H, an alkyl, aralkyl, or aryl radical with up to 19 carbon atoms, and R ₄ and R ₅ are independent, respectively. Then, H, OH, an alkyl, aralkyl, aryl, or acyl radical having a maximum of 19 carbon atoms, an N-acyldipeptide derivative or an isomer or salt thereof, and glyceryl dilaurate, steareth-10, and glycerin. A topical composition comprising a cosmetically acceptable topical carrier, comprising one or more of the above. A method of treating signs of skin aging, comprising topically applying a topical composition to the skin in which at least one sign of skin aging needs to be treated, said topical composition is the formula. :
R _1- Val-Ala-R ₂
In the formula, Val is valine, Ala is alanine, and R ₁ is an acyl radical having a maximum of 19 carbon atoms. , R ₂ is OR ₃ , NHR ₄ , or NHNHR ₅ , R ₃ is H, an alkyl, aralkyl, or aryl radical with up to 19 carbon atoms, and R ₄ and R ₅ are independent, respectively. The composition comprises H, OH, an N-acyldipeptide derivative or an isomer or salt thereof, which is an alkyl, aralkyl, aryl, or acyl radical having a maximum of 19 carbon atoms, and a glycolic acid. However, a method comprising up to about 10 weight percent glycolic acid. The signs of skin aging are wrinkles, fine wrinkles, deep wrinkles, loss of elasticity, uneven skin, stains, reduced skin thickness, and abnormal synthesis or synthetic reduction of collagen, glycosaminoglycans, proteoglycans, or elastin. The method according to claim 9, which is selected from the group consisting of. The method of claim 9, wherein the N-acyldipeptide derivative is administered topically to the skin with about 1 to about 8 weight percent glycolic acid. The dipeptide derivatives are N-Ac-Val-Ala-NH ₂ , N-Ac-Val-Ala-OH, N-Ac-Val-Ala-NHOH, N-Pr-Val-Ala-NH ₂ , and N-. The method of claim 9, wherein Ac is acetyl and Pr is propanoyl, selected from the group consisting of Pr-Val-Ala-OH. The method according to claim 9, wherein the N-acyldipeptide derivative is N-Ac-Val-Ala-NH ₂ , and in the formula, Ac is acetyl. formula:
R _1- Val-Ala-R ₂
A method for increasing the penetration of an N-acyldipeptide derivative or an isomer or salt thereof into the skin, wherein Val is valine, Ala is alanin, and R ₁ is up to 19 in the formula. R ₂ is OR ₃ , NHR ₄ , or NHNHR ₅ , and R ₃ is H, an alkyl, aralkyl, or aryl radical with up to 19 carbon atoms. R ₄ and R ₅ are independently H, OH, alkyl, aralkyl, aryl, or acyl radicals having up to 19 carbon atoms, the method being said to be a topical composition comprising glycolic acid. A method comprising topically administering an N-acyldipeptide derivative to the skin, wherein the amount of the glycolic acid is up to about 10% by weight of the composition. 14. The method of claim 14, wherein the N-acyldipeptide derivative is administered topically to the skin with about 1 to about 8 weight percent glycolic acid. The dipeptide derivatives are N-Ac-Val-Ala-NH ₂ , N-Ac-Val-Ala-OH, N-Ac-Val-Ala-NHOH, N-Pr-Val-Ala-NH ₂ , and N-. 14. The method of claim 14, wherein Ac is acetyl and Pr is propanoyl, selected from the group consisting of Pr-Val-Ala-OH. The method according to claim 14, wherein the N-acyldipeptide derivative is N-Ac-Val-Ala-NH ₂ , and in the formula, Ac is acetyl.